Treatment of oncogene-driven cancers

ABSTRACT

The present disclosure provides methods of treating a subject identified as having an oncogene driven cancer comprising administering to said subject an agent targeting the extracellular production of adenosine and/or an agent antagonizing the activation by adenosine of one of its receptors.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalApplication Ser. No. 62/817,425, filed Mar. 12, 2019, the entire contentof which is incorporated herein by reference.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

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REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

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BRIEF SUMMARY OF THE INVENTION

In some aspects, provided herein are methods of treating a subjectidentified as having an oncogene driven cancer comprising administeringto said subject an agent targeting the extracellular production ofadenosine and/or an agent antagonizing the activation by adenosine ofone of its receptors.

Other objects, features, and advantages of the present invention will beapparent to one of skill in the art from the following detaileddescription and figures.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1 CD73/TNAP ratio across pan-cancer TCGA. CD73 and TNAP expressionwas derived from pan-cancer TCGA atlas dataset. Numbers indicate ratioof log2 CPM values for CD73 and TNAP. Tumors on left are high in CD73and low in TNAP whereas tumors on right are high in TNAP and low inCD73.

FIG. 2A Identifying Oncogenic Drivers of CD73 Expression. Linear modelestimates adjusted for tumor type of alterations in cancer driver genesthat predict CD73 expression.

FIG. 2B and FIG. 2C plots CD73 expression in representative examples ofoncogenic cancer drivers, KRAS (B) and TBL1XR1 (C). The plot on the leftis WT expression, the plot on the right is mutant expression of thereferenced oncogenic cancer driver (ALT).

FIG. 2D and FIG. 2E Identification of oncogenic regulators of adenosinepathway genes. Positive regulators of CD73 (D) and negative regulatorsof CD73 (E) are plotted where the X-axis denotes the oncogene from panelA, and the Y-axis shows linear model estimates adjusted for tumor typefor particular adenosine pathway genes.

FIG. 3A-D displays Forest plot showing hazard ratio with 95% confidenceintervals adjusted for tumor type for CD73 expression in WT (A, B) andmutated (ALT) (C, D) patients for each cancer driver forprogression-free survival in pan-cancer TCGA dataset. The X-axis is theHazard ratio, while the Y-axis lists different oncogenic proteins. Thehazard ratio displayed herein is the exponent of the coefficient derivedfrom Cox-regression model. The p-value also comes from the same modeldenoting if the survival difference between the WT and ALT groups issignificant.

FIG. 3E shows a Kaplan-Meier curve of CD73 expression in EGFR mutantversus wild-type patients. The X-axis denotes time in years, while theY-axis denotes probably of patients that have progression-free survival.Patients with EGFR ALT and High CD73 have the worst survival rate, whileEGFR ALT and low CD73 had a survival rate that was closer to EGFR WTpatients.

FIG. 4A and FIG. 4B Association of pembrolizumab response and mutationstatus of cancer drivers regulating CD73 in NSCLC. Panel A and B showStacked barplot for cancer driver alterations positively and negativelyassociated with CD73 from FIG. 1. Y-axis denotes percentage of patientsthat achieve or do not achieve durable clinical benefit beyond 6 monthswith pembrolizumab. X-axis denotes WT and ALT for each listed oncogenicdriver.

FIG. 4C displays a Forest plot of progression-free survival denotinghazard ratio for cancer drivers that are positive and negativeregulators of CD73. The X-axis denotes the Hazard Ratio, and the Y-axislists particular oncogenic drivers. The dazard ratio displayed herein isthe exponent of the coefficient derived from Cox-regression model. Thep-value also comes from the same model denoting if the survivaldifference between the WT and ALT groups is significant.

DETAILED DESCRIPTION OF THE INVENTION

I. General

The present disclosure is drawn to the discovery that oncogene drivencancers (i.e., cancers where at least one gene involved in normal cellgrowth is mutated) often alter the expression levels of one or moreproteins involved in the extracellular production of adenosine and/orthe expression levels of one or more adenosine receptor signalingproteins. Altered expression levels of these proteins can cause anincrease in the amount of adenosine in the tumor microenvironment and/orover-activation of adenosine-mediated signaling pathways. The presenceof increased levels of adenosine and the activation of particularadenosine-mediated signaling pathways in the tumor microenvironment hasbeen shown to provide an immunosuppressive effect in tumor models. Thus,subjects identified as having an oncogene driven cancer are primecandidates for therapy with an agent targeting a protein involved in theextracellular production of adenosine and/or an agent antagonizing theactivation by adenosine of one of its receptors. Advantageously, byadministering one or more of these agents, the effect of the alteredexpression of a protein involved in the production of extracellularadenosine and/or adenosine-mediated signaling can be reduced, minimized,or eliminated. As a non-limiting example, EGFR, BRAF, and KRAS mutationseach upregulate CD73 expression, which will increase the local levels ofadenosine. Administering a CD73 inhibitor will provide a positiveclinical benefit by reducing or eliminating the effects of theunregulated CD73 levels in these cancer types.

II. Definitions

Unless otherwise indicated, the following terms are intended to have themeaning set forth below. Other terms are defined elsewhere throughoutthe specification.

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbonradical, having the number of carbon atoms designated (i.e. Ci-s meansone to eight carbons). Alkyl can include any number of carbons, such asC₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₁₋₆, C₁₋₇, C₁₋₈, C₁₋₉, C₁₋₁₀, C₂₋₃, C₂₋₄, C₂₋₅,C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆ and C₅₋₆. Examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

The term “alkylene” refers to a straight or branched, saturated,aliphatic radical having the number of carbon atoms indicated, andlinking at least two other groups, i.e., a divalent hydrocarbon radical.The two moieties linked to the alkylene can be linked to the same atomor different atoms of the alkylene group. For instance, a straight chainalkylene can be the bivalent radical of —(CH₂)_(n)—, where n is 1, 2, 3,4, 5 or 6. Representative alkylene groups include, but are not limitedto, methylene, ethylene, propylene, isopropylene, butylene, isobutylene,sec-butylene, pentylene and hexylene. Alkylene groups, often referred toas X¹ or X² groups in the present application, can be substituted orunsubstituted. When a group comprising X¹ or X² is optionallysubstituted, it is understood that the optional substitutions may be onthe alkylene portion of the moiety.

The term “cycloalkyl” refers to hydrocarbon rings having the indicatednumber of ring atoms (e.g., C₃₋₆ cycloalkyl) and being fully saturatedor having no more than one double bond between ring vertices.“Cycloalkyl” is also meant to refer to bicyclic and polycyclichydrocarbon rings such as, for example, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, etc. In some embodiments, the cycloalkyl compoundsof the present disclosure are monocyclic C₃₋₆ cycloalkyl moieties.

The term “heterocycloalkyl” refers to a cycloalkyl ring having theindicated number of ring vertices (or members) and having from one tofive heteroatoms selected from N, O, and S, which replace one to five ofthe carbon vertices, and wherein the nitrogen and sulfur atoms areoptionally oxidized, and the nitrogen atom(s) are optionallyquaternized. The cycloheteroalkyl may be a monocyclic, a bicyclic or apolycylic ring system. Non limiting examples of cycloheteroalkyl groupsinclude pyrrolidine, imidazolidine, pyrazolidine, butyrolactam,valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide,piperidine, 1,4-dioxane, morpholine, thiomorpholine,thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran,pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran,tetrhydrothiophene, quinuclidine, and the like. A cycloheteroalkyl groupcan be attached to the remainder of the molecule through a ring carbonor a heteroatom.

As used herein, a wavy line, “

”, that intersects a single, double or triple bond in any chemicalstructure depicted herein, represent the point attachment of the single,double, or triple bond to the remainder of the molecule. Additionally, abond extending to the center of a ring (e.g., a phenyl ring) is meant toindicate attachment at any of the available ring vertices. One of skillin the art will understand that multiple substituents shown as beingattached to a ring will occupy ring vertices that provide stablecompounds and are otherwise sterically compatible. For a divalentcomponent, a representation is meant to include either orientation(forward or reverse).

For example, the group “—C(O)NH—” is meant to include a linkage ineither orientation: —C(O)NH— or —NHC(O)—, and similarly, “—O—CH₂CH₂—” ismeant to include both —O—CH₂CH₂— and —CH₂CH₂—O—.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₄haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon group which can be a single ring ormultiple rings (up to three rings) which are fused together or linkedcovalently. Non-limiting examples of aryl groups include phenyl,naphthyl and biphenyl.

The term “heteroaryl” refers to aryl groups (or rings) that contain fromone to five heteroatoms selected from N, O, and S, wherein the nitrogenand sulfur atoms are optionally oxidized, and the nitrogen atom(s) areoptionally quaternized. A heteroaryl group can be attached to theremainder of the molecule through a heteroatom. Non-limiting examples ofheteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl,triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl,benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl,benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl,imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl,quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl,pyrrolyl, thiazolyl, furyl, thienyl and the like. Substituents for aheteroaryl ring can be selected from the group of acceptablesubstituents described below.

The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in someembodiments, will be optionally substituted. Selected substituents foreach type of radical are provided below.

Optional substituents for the alkyl radicals (including those groupsoften referred to as alkylene, alkenyl, and alkynyl) can be a variety ofgroups selected from: halogen, —OR′—, —NR′R—SR′, —SiR′R″R′″, —OC(O)R′,—C(O)R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR″C(O)₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —CN (cyano), —NO₂, aryl, aryloxy,oxo, cycloalkyl and heterocycloalkyl in a number ranging from zero to (2m′+1), where m′ is the total number of carbon atoms in such radical. R′,R″ and R′″ each independently refer to hydrogen, unsubstituted C₁₋₈alkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, C₁₋₈alkoxy or C₁₋₈ thioalkoxy groups, or unsubstituted aryl-C₁₋₄ alkylgroups. When R′ and R″ are attached to the same nitrogen atom, they canbe combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or7-membered ring. For example, —NR′R″ is meant to include 1-pyrrolidinyland 4-morpholinyl.

Optional substituents for the cycloalkyl and heterocycloalkyl radicalscan be a variety of groups selected from: alkyl optionally substitutedwith C(O)OR′, halogen, —OR′, —NR′R—SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′,—CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NH—C(NH₂)═NH, —NR′C(NH₂)═NH, C(NH₂)═NR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NR′S(O)₂R″, —CN (cyano), —NO₂, aryl, aryloxy and oxo. R′,R″ and R′″ each independently refer to hydrogen, unsubstituted C₁₋₈alkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, C₁₋₈alkoxy or C₁₋₈ thioalkoxy groups, or unsubstituted aryl-C₁₋₄ alkylgroups.

Similarly, optional substituents for the aryl and heteroaryl groups arevaried and are generally selected from: -halogen, —OR′, —OC(O)R′,—NR′R—SR′, —R′, —CN, —NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″,—NR″C(O)R′, —NR″C(O)₂R′, —NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —N₃,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R′″ are independently selected fromhydrogen, C₁₋₈ alkyl, C₁₋₈haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl andC₂₋₈ alkynyl. Other suitable substituents include each of the above arylsubstituents attached to a ring atom by an alkylene tether of from 1-6carbon atoms.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula—T—C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂-or a single bond, and q is an integer of from 0 to 2.

Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —A—(CR^(f)R^(g))_(r)—B—, wherein A and B are independently—CH₂—, —O—, —NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, ris an integer of from 1 to 3, and R^(f) and R^(g) are each independentlyH of halogen. One of the single bonds of the new ring so formed mayoptionally be replaced with a double bond. Alternatively, two of thesubstituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted C₁₋₆ alkyl.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occuring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al, “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention. Inaddition to salt forms, the present invention provides compounds whichare in a prodrug form. Prodrugs of the compounds described herein arethose compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent. Prodrugs aredescribed in more detail elsewhere herein.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention. When a stereochemical depiction is shown, it is meantto refer the compound in which one of the isomers is present andsubstantially free of the other isomer.

‘Substantially free of’ another isomer indicates at least an 80/20 ratioof the two isomers, more preferably 90/10, or 95/5 or more. In someembodiments, one of the isomers will be present in an amount of at least99%.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. Unnatural proportions of an isotope may bedefined as ranging from the amount found in nature to an amountconsisting of 100% of the atom in question. For example, the compoundsmay incorporate radioactive isotopes, such as for example tritium (³H),iodine-125 (¹²⁵I) or carbon-14 (¹⁴C), or non-radioactive isotopes, suchas deuterium (²H) or carbon-13 (¹³C). Such isotopic variations canprovide additional utilities to those described elsewhere within thisapplication. For instance, isotopic variants of the compounds of theinvention may find additional utility, including but not limited to, asdiagnostic and/or imaging reagents, or as cytotoxic/radiotoxictherapeutic agents. Additionally, isotopic variants of the compounds ofthe invention can have altered pharmacokinetic and pharmacodynamiccharacteristics which can contribute to enhanced safety, tolerability orefficacy during treatment. All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are intended to beencompassed within the scope of the present invention.

The terms “patient” or “subject” are used interchangeably to refer to ahuman or a non-human animal (e.g., a mammal).

The terms “administration”, “administer” and the like, as they apply to,for example, a subject, cell, tissue, organ, or biological fluid, referto contact of, for example, an inhibitor of A2aR/A2bR (or anotherinhibitor or antagonist described herein) or a pharmaceuticalcomposition comprising same to the subject, cell, tissue, organ, orbiological fluid. In the context of a cell, administration includescontact (e.g., in vitro or ex vivo) of a reagent to the cell, as well ascontact of a reagent to a fluid, where the fluid is in contact with thecell.

The terms “treat”, “treating”, treatment” and the like refer to a courseof action (such as administering an inhibitor of A2aR/A2bR or anotherinhibitor or antagonist described herein) initiated after a disease,disorder or condition, or a symptom thereof, has been diagnosed,observed, and the like so as to eliminate, reduce, suppress, mitigate,or ameliorate, either temporarily or permanently, at least one of theunderlying causes of a disease, disorder, or condition afflicting asubject, or at least one of the symptoms associated with a disease,disorder, condition afflicting a subject. Thus, treatment includesinhibiting (e.g., arresting the development or further development ofthe disease, disorder or condition or clinical symptoms associationtherewith) an active disease.

The term “in need of treatment” as used herein refers to a judgment madeby a physician or other caregiver that a subject requires or willbenefit from treatment. This judgment is made based on a variety offactors that are in the realm of the physician's or caregiver'sexpertise.

The terms “prevent”, “preventing”, “prevention” and the like refer to acourse of action (such as administering an A2aR/A2bR inhibitor oranother inhibitor or antagonist described herein) initiated in a manner(e.g., prior to the onset of a disease, disorder, condition or symptomthereof) so as to prevent, suppress, inhibit or reduce, eithertemporarily or permanently, a subject's risk of developing a disease,disorder, condition or the like (as determined by, for example, theabsence of clinical symptoms) or delaying the onset thereof, generallyin the context of a subject predisposed to having a particular disease,disorder or condition. In certain instances, the terms also refer toslowing the progression of the disease, disorder or condition orinhibiting progression thereof to a harmful or otherwise undesiredstate.

The term “in need of prevention” as used herein refers to a judgmentmade by a physician or other caregiver that a subject requires or willbenefit from preventative care. This judgment is made based on a varietyof factors that are in the realm of a physician's or caregiver'sexpertise.

The phrase “therapeutically effective amount” refers to theadministration of an agent to a subject, either alone or as part of apharmaceutical composition and either in a single dose or as part of aseries of doses, in an amount capable of having any detectable, positiveeffect on any symptom, aspect, or characteristic of a disease, disorderor condition when administered to the subject. The therapeuticallyeffective amount can be ascertained by measuring relevant physiologicaleffects, and it can be adjusted in connection with the dosing regimenand diagnostic analysis of the subject's condition, and the like. By wayof example, measurement of the serum level of an A2aR/A2bR inhibitor(or, e.g., another inhibitor or antagonist described herein) at aparticular time post-administration may be indicative of whether atherapeutically effective amount has been used.

The phrase “in a sufficient amount to effect a change” means that thereis a detectable difference between a level of an indicator measuredbefore (e.g., a baseline level) and after administration of a particulartherapy. Indicators include any objective parameter (e.g., serumconcentration) or subjective parameter (e.g., a subject's feeling ofwell-being).

The term “small molecules” refers to chemical compounds having amolecular weight that is less than about 10 kDa, less than about 2 kDa,or less than about 1 kDa. Small molecules include, but are not limitedto, inorganic molecules, organic molecules, organic molecules containingan inorganic component, molecules comprising a radioactive atom, andsynthetic molecules. Therapeutically, a small molecule may be morepermeable to cells, less susceptible to degradation, and less likely toelicit an immune response than large molecules.

The term “ligand” refers to, for example, a peptide, a polypeptide, amembrane-associated or membrane-bound molecule, or a complex thereof,that can act as an agonist or antagonist of a receptor. A ligandencompasses natural and synthetic ligands, e.g., cytokines, cytokinevariants, analogs, muteins, and binding compositions derived fromantibodies, as well as small molecules. The term also encompasses anagent that is neither an agonist nor antagonist, but that can bind to areceptor without significantly influencing its biological properties,e.g., signaling or adhesion. Moreover, the term includes amembrane-bound ligand that has been changed by, e.g., chemical orrecombinant methods, to a soluble version of the membrane-bound ligand.A ligand or receptor may be entirely intracellular, that is, it mayreside in the cytosol, nucleus, or some other intracellular compartment.The complex of a ligand and receptor is termed a “ligand-receptorcomplex.”

The terms “inhibitors” and “antagonists”, or “activators” and “agonists”refer to inhibitory or activating molecules, respectively, for example,for the activation of, e.g., a ligand, receptor, cofactor, gene, cell,tissue, or organ. Inhibitors are molecules that decrease, block,prevent, delay activation, inactivate, desensitize, or down-regulate,e.g., a gene, protein, ligand, receptor, or cell. Activators aremolecules that increase, activate, facilitate, enhance activation,sensitize, or up-regulate, e.g., a gene, protein, ligand, receptor, orcell. An inhibitor may also be defined as a molecule that reduces,blocks, or inactivates a constitutive activity. An “agonist” is amolecule that interacts with a target to cause or promote an increase inthe activation of the target. An “antagonist” is a molecule that opposesthe action(s) of an agonist. An antagonist prevents, reduces, inhibits,or neutralizes the activity of an agonist, and an antagonist can alsoprevent, inhibit, or reduce constitutive activity of a target, e.g., atarget receptor, even where there is no identified agonist.

The terms “modulate”, “modulation” and the like refer to the ability ofa molecule (e.g., an activator or an inhibitor) to increase or decreasethe function or activity of an adenosine related protein describedherein, either directly or indirectly. A modulator may act alone, or itmay use a cofactor, e.g., a protein, metal ion, or small molecule.Examples of modulators include small molecule compounds and otherbioorganic molecules. Numerous libraries of small molecule compounds(e.g., combinatorial libraries) are commercially available and can serveas a starting point for identifying a modulator. The skilled artisan isable to develop one or more assays (e.g., biochemical or cell-basedassays) in which such compound libraries can be screened in order toidentify one or more compounds having the desired properties;thereafter, the skilled medicinal chemist is able to optimize such oneor more compounds by, for example, synthesizing and evaluating analogsand derivatives thereof Synthetic and/or molecular modeling studies canalso be utilized in the identification of an Activator.

The “activity” of a molecule may describe or refer to the binding of themolecule to a ligand or to a receptor; to catalytic activity; to theability to stimulate gene expression or cell signaling, differentiation,or maturation; to antigenic activity; to the modulation of activities ofother molecules; and the like. The term “proliferative activity”encompasses an activity that promotes, that is necessary for, or that isspecifically associated with, for example, normal cell division, as wellas cancer, tumors, dysplasia, cell transformation, metastasis, andangiogenesis.

As used herein, “comparable”, “comparable activity”, “activitycomparable to”, “comparable effect”, “effect comparable to”, and thelike are relative terms that can be viewed quantitatively and/orqualitatively. The meaning of the terms is frequently dependent on thecontext in which they are used. By way of example, two agents that bothactivate a receptor can be viewed as having a comparable effect from aqualitative perspective, but the two agents can be viewed as lacking acomparable effect from a quantitative perspective if one agent is onlyable to achieve 20% of the activity of the other agent as determined inan art-accepted assay (e.g., a dose-response assay) or in anart-accepted animal model. When comparing one result to another result(e.g., one result to a reference standard), “comparable” frequently(though not always) means that one result deviates from a referencestandard by less than 35%, by less than 30%, by less than 25%, by lessthan 20%, by less than 15%, by less than 10%, by less than 7%, by lessthan 5%, by less than 4%, by less than 3%, by less than 2%, or by lessthan 1%. In particular embodiments, one result is comparable to areference standard if it deviates by less than 15%, by less than 10%, orby less than 5% from the reference standard. By way of example, but notlimitation, the activity or effect may refer to efficacy, stability,solubility, or immunogenicity.

“Substantially pure” indicates that a component makes up greater thanabout 50% of the total content of the composition, and typically greaterthan about 60% of the total polypeptide content. More typically,“substantially pure” refers to compositions in which at least 75%, atleast 85%, at least 90% or more of the total composition is thecomponent of interest. In some cases, the polypeptide will make upgreater than about 90%, or greater than about 95% of the total contentof the composition.

The terms “specifically binds” or “selectively binds”, when referring toa ligand/receptor, antibody/antigen, or other binding pair, indicates abinding reaction which is determinative of the presence of the proteinin a heterogeneous population of proteins and other biologics. Thus,under designated conditions, a specified ligand binds to a particularreceptor and does not bind in a significant amount to other proteinspresent in the sample. The antibody, or binding composition derived fromthe antigen-binding site of an antibody, of the contemplated methodbinds to its antigen, or a variant or mutein thereof, with an affinitythat is at least two-fold greater, at least ten times greater, at least20-times greater, or at least 100-times greater than the affinity withany other antibody, or binding composition derived therefrom. In aparticular embodiment, the antibody will have an affinity that isgreater than about 10⁹ liters/mol, as determined by, e.g., Scatchardanalysis (Munsen, et al. 1980 Analyt. Biochem. 107:220-239).

The term “response,” for example, of a cell, tissue, organ, or organism,encompasses a change in biochemical or physiological behavior, e.g.,concentration, density, adhesion, or migration within a biologicalcompartment, rate of gene expression, or state of differentiation, wherethe change is correlated with activation, stimulation, or treatment, orwith internal mechanisms such as genetic programming. In certaincontexts, the terms “activation”, “stimulation”, and the like refer tocell activation as regulated by internal mechanisms, as well as byexternal or environmental factors; whereas the terms “inhibition”,“down-regulation” and the like refer to the opposite effects.

The term “oncogene driven cancer” refers to various malignant neoplasmscharacterized by having at least one gene involved in normal cell growththat is mutated. Genes involved in normal cell growth include, but arenot limited to KRAS, BRAF, MET, FUBP1, RAC1, EGFR, CDK4, CTCF, PGR, RET,RASA1, JAK1, PHF6, NF1, CIC, ARID1A, ZFHX3, ZCCHC12, GNA11, SMAD4,USP9X, CDKN2A, FAT1, PIK3R1, SCAF4, PMS2, RNF43, SMC1A, BCOR, FGFR2,COL5A1, ATM, KMT2B, CTNNB1, MYC, RAD21, PTEN, AXL, HIF1/2A, PAK4, RHOB,TBL1XR1, KEAP1, ZFP36L2, FGFR3, FOXA1, FLT3, TRAF3, RNF111, PPP2R1A,TXNIP, STAG2, RIT1, TGIF1, FOXQ1, ATR, CYSLTR2, PCBP1, PIK3R2, ASXL1,HIST1H1C, KLF5, PIK3CB, SPOP, MECOM, CACNA1A, CTNND1, DACH1, XPO1,ZNF750, FBXW7, MUC6, KDM6A, GATA3, ZBTB20, PIK3CA, RB1, SOX17, SMARCA4,KIT, CHD8, CHD4, and APOB. A mutation in a gene involved in normal cellgrowth often alters the expression levels of one or more proteinsinvolved in the extracellular production of adenosine and/or theexpression levels of one or more adenosine receptor signaling proteins.These proteins include, but are not limited to adenosine A2a receptor(A2aR), adenosine A2b receptor (A2bR), adenosine Al receptor (A1R),tissue-nonspecific alkaline phosphatase (TNAP), CD73, ectonucleotidepyrophosphatase/phosphodiesterase 1 (ENPP1), CD38, and/or CD39.

The term “agent targeting the extracellular production of adenosine”refers to modulators of one or more proteins involved in theextracellular production of adenosine. Exemplary modulators includesmall molecule compounds, antibodies, and interfering RNA.

Proteins involved in the extracellular production of adenosine include,but are not limited to tissue-nonspecific alkaline phosphatase (TNAP),CD73, ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), CD38,and/or CD39. Thus, modulators known to target these proteins arerelevant to the current disclosure.

The term “agent antagonizing the activation by adenosine of one of itsreceptors” refers to antagonists that reduce or fully prevent adenosinefrom binding with an adenosine receptor protein, often an integralmembrane protein. Protein receptors that are activated by adenosineinclude, but are not limited to, adenosine Al receptor (A1R), adenosineA2a receptor (A2aR) and/or adenosine A2b receptor (A2bR). Thus,antagonists known to target these receptors are relevant to the currentdisclosure.

III. Detailed Description of Embodiments

Provided herein, for example, are methods of a subject identified ashaving an oncogene driven cancer comprising administering to saidsubject an agent targeting the extracellular production of adenosineand/or an agent antagonizing the activation by adenosine of one of itsreceptors.

Oncogene Driven Cancers

Oncogene driven cancers refers to various malignant neoplasmscharacterized by having at least one gene involved in normal cell growththat is mutated. As demonstrated herein, a pan-cancer analysis of TheCancer Genome Atlas (TCGA) demonstrates that particular mutatedoncogenes in oncogene driven cancers act as regulators of proteins inthe adenosine pathway as well as adenosine receptor signaling proteins,altering their expression levels. As previously stated, increasedadenosine levels and/or over activation of particular adenosine-mediatedsignaling pathways in the tumor microenvironment provide animmunosuppressive effect. Thus, the methods described herein assistmedical practitioners by advantageously identifying suitable treatmentoptions that improve a subject's response to therapy based on theoncogene driven cancer in a subject.

There are a number of known oncogenes, and the disclosure hereinestablishes the correlation between certain oncogenes and alteredexpression levels of proteins involved in the extracellular productionof adenosine and/or altered expression levels of one or more adenosinereceptor signaling proteins. Therefore, subjects suitable for thetreatments described herein include those identified as having anoncogene driven cancer with a mutation in at least one gene selectedfrom the group consisting of KRAS, BRAF, MET, FUBP1, RAC1, EGFR, CDK4,CTCF, PGR, RET, RASA1, JAK1, PHF6, NF1, CIC, ARID1A, ZFHX3, ZCCHC12,GNA11,

SMAD4, USP9X, CDKN2A, FAT1, PIK3R1, SCAF4, PMS2, RNF43, SMC1A, BCOR,FGFR2, COL5A1, ATM, KMT2B, CTNNB1, MYC, RAD21, PTEN, AXL, HIF1/2A, PAK4,RHOB, TBL1XR1, KEAP1, ZFP36L2, FGFR3, FOXA1, FLT3, TRAF3, RNF111,PPP2R1A, TXNIP, STAG2, RIT1, TGIF1, FOXQ1, ATR, CYSLTR2, PCBP1, PIK3R2,ASXL1, HIST1H1C, KLF5, PIK3CB, SPOP, MECOM, CACNA1A, CTNND1, DACH1,XPO1, ZNF750, FBXW7, MUC6, KDM6A, GATA3, ZBTB20, PIK3CA, RB1, SOX17,SMARCA4, KIT, CHD8, CHD4, and APOB.

In some embodiments, the subject identified as having an oncogene drivencancer has a mutation in at least one gene selected from the groupconsisting of KRAS, BRAF, MET, FUBP1, RAC1, EGFR, CDK4, CTCF, PGR, RET,RASA1, JAK1, PHF6, NF1, CIC, ARID1A, ZFHX3, ZCCCHC12, GNA11, SMAD4,USP9X, CDKN2A, FAT1, PIK3R1, SCAF4, PMS2, RNF43, SMC1A, BCOR, FGFR2,COL5A1, ATM, KMT2B, CTNNB1, MYC, RAD21, PTEN, AXL, HIF1/2A, and PAK4.

In some embodiments, the subject identified as having an oncogene drivencancer has a mutation in at least one gene selected from the groupconsisting of EGFR, KRAS, BRAF, MET, FUBP1, CDK4, CTCF, PGR, RET, RASA1,JAK1, NF1, CIC, ARID1A, ZFHX3, SMAD4, USP9X, CDKN2A, FAT1, and ATM.

In some embodiments, the subject identified as having an oncogene drivencancer has a mutation in at least one gene selected from the groupconsisting of MYC, PMS2, CTNNB1, and SMAD4.

In some embodiments, the subject identified as having an oncogene drivencancer has a mutation in at least one gene selected from the groupconsisting of KRAS, BRAF, RASA1, AXL, HIF1/2A, PAK4, and RAC1.

In some embodiments, the subject identified as having an oncogene drivencancer has a mutation in at least one gene selected from the groupconsisting of EGFR, KRAS, and BRAF.

Mutations in the oncogenes described above can be tested and identifiedusing known laboratory techniques and commercially available kits. Forexample, SNP arrays, Foundation One test by Foundation Medicine,RNAsequencing or whole genome/exome sequencing. These mutations can beidentified using multiple modalities like variant calling algorithmssuch as Mutect2, Varscan, RADIA etc (Ellrott K et.al Cell Systems 2018).

In some embodiments, the present disclosure provides methods fortreating a subject identified as having an oncogene driven cancer withan agent that targets the extracellular production of adenosine and/oran agent antagonizing the activation by adenosine of one of itsreceptors with at least one additional therapeutic, examples of whichare set forth elsewhere herein.

In some embodiments, the cancer is non-responsive to PD-1 and/or PD-L1treatment.

Agents Targeting the Extracellular Production of Adenosine

A number of proteins are known to be involved in the extracellularproduction of adenosine in the body. For example, a dominant pathwayleading to the generation of extracellular adenosine is the sequentialdephosphorylation of ATP by CD39, which hydrolyzes ATP to ADP and thenAMP, and CD73, which hydrolyzes AMP to adenosine. TNAP also contributesto the production of adenosine from AMP. An alternative mechanismleading to the generation of extracellular adenosine is the hydrolysisof NAD+ to ADPR by CD38, and ADPR to AMP by ENPP1. ENPP1 may alsohydrolyze NAD+ to produce AMP. Thus, proteins involved in theextracellular production of adenosine include, but are not limited totissue-nonspecific alkaline phosphatase (TNAP), CD73, ectonucleotidepyrophosphatase/phosphodiesterase 1 (ENPP1), CD38, and/or CD39. Asdiscussed above, mutations in one or more oncogenes can alter theexpression levels of one or more proteins involved in the production ofadenosine. Thus, agents that can modulate the activity of proteinsinvolved in the production of adenosine are useful because they can beused to reduce or eliminate the effects of altered protein expressionand increased adenosine levels caused by oncogene driven cancers.

As contemplated herein, the present disclosure provides method oftreating an oncogene driven cancer in a subject using one or more agentsthat target the extracellular production of adenosine.

Tissue-nonspecific alkaline phosphatase (TNAP) inhibitors. Several TNAPinhibitors are known in the art. In some embodiments, the TNAP inhibitoruseful in the described methods is an agent disclosed in WO/2013/126608,WO/2006/039480, or WO/2002/092020, the contents of each is herebyincorporated by reference for all purposes.

CD 73 Inhibitors. In some embodiments, the CD73 inhibitors useful in thedescribed methods are compounds of Formula (i)

or a pharmaceutically acceptable salt, hydrate, or solvate thereof,wherein,

-   -   each R¹ is independently selected from the group consisting of        hydrogen, optionally substituted C₁-C₆ alkyl, optionally        substituted aryl, and —C(R²R²)—O—C(O)—OR³, or two R¹ groups are        optionally combined to form a 5- to 7-membered ring;    -   each R² is independently selected from the group consisting of H        and optionally substituted C₁-C₆ alkyl;    -   each R³ is independently selected from the group consisting of        H, C₁-C₆ alkyl, and optionally substituted aryl;    -   R⁵ is selected from the group consisting of H and optionally        substituted C₁-C₆ alkyl;    -   X is selected from the group consisting of O, CH₂, and S;    -   A is selected from the group consisting of:

-   -   each of which is optionally substituted with from 1 to 5 R⁶        substituents, and wherein the subscript n is an integer from 0        to 3;    -   Z is selected from the group consisting of CH₂, CHR⁶, NR⁶, and        O;    -   each R⁶ is independently selected from the group consisting of        H, CH₃, OH, CN, F, optionally substituted C₁-C₆ alkyl, and        OC(O)—C₁-C₆ alkyl; and optionally two R⁶ groups on adjacent ring        vertices are joined together to form a 5- to 6-membered ring        having at least one heteroatom as a ring vertex; and    -   Het is selected from the group consisting of:

wherein the wavy line indicates the point of attachment to the remainderof the compound, and wherein:

-   -   R^(a) is selected from the group consisting of H, NH₂, NHR⁷,        NHC(O)R⁷, NR⁷R⁷, R⁷, OH, SR⁷ and OR⁷;    -   R^(b) is selected from the group consisting of H, halogen, NH₂,        NHR⁷, NR⁷R⁷, R⁷, OH, and OR⁷;    -   R^(c) and R^(d) are independently selected from the group        consisting of H, halogen, haloalkyl, NH₂, NHR⁷, NR⁷R⁷, R⁷, OH,        OR⁷, SR⁷,    -   SO₂R⁷, —X¹—NH₂, —X¹—NHR⁷, —X¹—NR⁷R⁷, —X¹—OH, —X¹—OR⁷, —X¹—SR⁷        and —X¹—SO₂R⁷;    -   R^(e) and R^(f) are independently selected from the group        consisting of H, halogen, and optionally substituted C₁-C₆        alkyl;    -   each X¹ is C₁-C₄alkylene; and    -   each R⁷ is independently selected from the group consisting of        optionally substituted C₁-C₁₀ alkyl, optionally substituted        C₂-C₁₀ alkenyl, optionally substituted C₂-C₁₀ alkynyl,        optionally substituted C₃-C₇ cycloalkyl, optionally substituted        C₃-C₇ cycloalkylC₁-C₄alkyl, optionally substituted 4-7 membered        cycloheteroalkyl, optionally substituted 4-7 membered        cycloheteroalkylC₁-C₄alkyl, optionally substituted aryl,        optionally substituted arylC₁-C₄alkyl, optionally substituted        arylC₂-C₄alkenyl, optionally substituted arylC₂-C₄alkynyl,        optionally substituted heteroaryl, optionally substituted        heteroarylC₁-C₄alkyl, optionally substituted        heteroarylC₁-C₄alkenyl, optionally substituted        heteroarylC₂-C₄alkynyl, and optionally, two R⁷ groups attached        to a nitrogen atom are joined together to form a 4- to        7-membered heterocyclic ring, optionally fused to an aryl ring;    -   with the proviso that the compounds are other than those        compounds wherein the combination of X, A, and Het results in

wherein R^(g) is H or the two R^(g) groups are combined to form anacetonide; and either

-   -   (1) R^(c) and R^(e) are hydrogen and R^(a) is —OEt, —OCH₂Ph,        —SCH₂Ph, —NH₂, methylamino, ethylamino, dimethylamino,        diethylamino, N-methyl-N-ethylamino, phenylamino, benzylamino,        2-phenylethylamino, N-benzyl-N-ethylamino, dibenzylamino,        4-aminobenzylamino, 4-chlorobenzylamino, 4-nitrobenzylamino, or        4-sulfamoylbenzylamino; or    -   (2) R^(c) is hydrogen, R^(a) is —NH₂, and R^(e) is bromo,        chloro, aminomethyl, or thioethyl; or    -   (3) R^(c) is hydrogen, R^(a) is benzylamino, and R^(e) is bromo.

In some embodiments, the CD73 inhibitor is Compound A

or a pharmaceutically acceptable salt thereof.

In some embodiments, the CD73 inhibitor is Compound B

or a pharmaceutically acceptable salt thereof.

In some embodiments, the CD73 inhibitor is Compound C

or a pharmaceutically acceptable salt thereof.

In some embodiments, the CD73 inhibitor is a molecule described in USPat. Pub. 2017/0267710 (see, US Appl. Ser. No. 15/400,748, filed on June6, 2017), the content of which is hereby incorporated by reference forall purposes.

In some embodiments, the CD73 inhibitor is an agent disclosed inWO2015/164573, WO2017/120508, WO2018/183635, WO2018/094148,WO2018/119284, WO2018/183635, WO2018/208727, WO2018/208980,WO2017/098421, WO2017/153952, the contents of each is herebyincorporated by reference for all purposes.

In some embodiments, the CD73 inhibitor is Oleclumab (MEDI-9447),CPI-006, NZV930/SRF373, BMS-986179, or TJ4309.

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors.In some embodiments, the ectonucleotidepyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitor useful in thedescribed methods is MV-626.

In some embodiments, the ENPP1 inhibitor useful in the described methodsis an agent disclosed in WO2019/023635, the content of which is herebyincorporated by reference for all purposes.

CD 38 Inhibitors. In some embodiments, the CD38 inhibitors useful in thedescribed methods are Daratumumab or isatuximab.

In some embodiments, the CD38 inhibitor is an agent disclosed inWO/2019/034753, US2018/0298106, WO2019/034752, the content of each ishereby incorporated by reference for all purposes.

CD 39 Inhibitors. CD39 is also known as ectonucleoside triphosphatediphosphohydrolase-1. In some embodiments, the CD39 inhibitor useful inthe described methods is IPH5201, SRF617, or TTX-030.

In some embodiments, the CD39 inhibitor is an agent disclosed inWO2012/085132, WO2017/089334, WO2009/095478, WO2011/154453, andWO2018/224685, the content of each is hereby incorporated by referencefor all purposes.

The present disclosure encompasses pharmaceutically acceptable salts, orderivatives of any of the above.

Agents Antagonizing the Activation by Adenosine of One of Its Receptors

There are a number of receptors in the body that are activated byextracellular adenosine. That is, the binding of adenosine initiates anenzymatic activity and/or propagates a cellular signal. Activation byadenosine occurs via four G-coupled adenosine receptors: A1, A2a, A2band A3. Adenosine largely signals through the A2a receptor (expressedprimarily on T cells) and A2b receptor (expressed on myloid cells),which stimulated by adenosine, leads to impaired T-cell activation.While less understood, the A1 receptor has been reported to be involvedin the pathogenesis of cancers such as breast, colon and gastriccancers, and the A3 receptor has been reported to be involved incolorectal and breast cancer. The over activation activation of one ormore of these receptors by adenosine in a tumor microenvironment canlead to immunosuppressive effects. Thus, antagonists that can block orotherwise prevent the binding of adenosine to these receptors are usefulin the treatment of oncogene driven cancers. Relevant receptors include,but are not limited to the adenosine Al receptor (A1R), the adenosineA2a receptor (A2aR) and/or the adenosine A2b receptor, and the adenosineA3 receptor (A3R).

As contemplated herein, the present disclosure provides method oftreating an oncogene driven cancer using one or more agents thatantagonizing the activation by adenosine of one of its receptors.

Adenosine Al Receptor (A1R) Antagonists. In some embodiments, the A1Rantagonist useful in the described methods is FK352, KW-3902(Rolofylline), SLV320, BG9719 (CVT-124), or BG9928 (Adentri).

Adenosine A2a Receptor (A2aR) and/or Adenosine A2b Receptor (A2bR)Antagonists. In some embodiments, the adenosine A2a receptor (A2aR)and/or adenosine A2b receptor (A2bR) antagonists useful in the describedmethods are compounds of Formula (I)

or a pharmaceutically acceptable salt, hydrate, or solvate thereof,wherein,

-   -   G¹ is N or CR³′;    -   G² is N or CR^(3b);    -   G³ is N or CR³′;    -   R^(3a), R^(3b), and R^(3c) are each independently H or C₁₋₃        alkyl;    -   R^(1a) and R^(1b) are each independently selected from the group        consisting of        -   i) H        -   ii) C₁₋₈ alkyl optionally substituted with from 1-3 R⁵            substituents,        -   iii) —X¹—O—C₁₋₈ alkyl optionally substituted with from 1-3            R⁵ substituents,        -   iv) —C(O)—R⁶,        -   v) Y optionally substituted with 1-3 R⁷ substituents, and        -   vi) —X¹—Y optionally substituted with 1-3 R⁷ substituents;            or        -   vii) R^(1a) and R^(1b) together with the nitrogen to which            they are attached form a 5-6 membered heterocycloalkyl ring            optionally substituted with from 1-3 R⁸ substituents,            wherein the heterocycloalkyl has 0-2 additional heteroatom            ring vertices selected from the group consisting of O, N,            and S;    -   each Y is C₃₋₈ cycloalkyl or 4 to 6-membered heterocycloalkyl        having 1-3 heteroatom ring vertices selected from the group        consisting of O, N, and S;    -   R² and R⁴ are each independently H or C₁₋₃ alkyl;    -   Ar¹ is phenyl or a 5 to 6-membered heteroaryl, each of which is        optionally substituted with 1-3 R⁹;    -   Ar² is phenyl or a 5 to 6-membered heteroaryl, each of which is        optionally substituted with 1-3 R¹⁰;    -   wherein the 5 to 6-membered heteroaryl of Ar¹ and Ar² each        independently have 1-3 heteroatom ring vertices selected from        the group consisting of O, N, and S;    -   each X¹ is C₁₋₆ alkylene;    -   each R⁵ is independently selected from the group consisting of        hydroxyl, C₃₋₈ cycloalkyl, phenyl, —O-phenyl, -C(O)OR^(a) and        oxo;    -   each R⁶ is C₁₋₈ alkyl or Y, each of which is optionally        substituted with 1-3 substituents selected from the group        consisting of hydroxyl, —O-phenyl, phenyl, and —O—C₁₋₈ alkyl;    -   each R⁷ is independently selected from the group consisting of        C₁₋₈ alkyl, hydroxyl, —O—C₁₋₈ alkyl, oxo, and C(O)OR^(a);    -   each R⁸ is independently selected from the group consisting of        C₁₋₈ alkyl, hydroxyl, and oxo;    -   each R⁹ is independently selected from the group consisting of        C₁₋₈ alkyl, —O—C₁₋₈ alkyl, —X¹—O—C₁₋₈ alkyl, —O—X¹—O—C₁₋₈ alkyl,        —X¹—O—X¹—O—C₁₋₈ alkyl, —C(O)OR^(a), halogen, cyano,        —NR^(b)R^(c), Y, —X¹—C₃₋₈ cycloalkyl, and —X²—Z, wherein X² is        selected from the group consisting of C₁₋₆ alkylene, —C₁₋₆        alkylene—O—, —C(O)—, and —S(O)₂—, Z is 4 to 6-membered        heterocycloalkyl having 1-3 heteroatom ring vertices selected        from the group consisting of O, N, and S, and wherein each of        said R⁹ substituents is optionally substituted with 1-3 R″;    -   each R¹⁰ is independently selected from the group consisting of        C₁₋₈ alkyl, halo, cyano, —O—C₁₋₈ alkyl, —X¹—O—C₁₋₈ alkyl,        —O—X¹—O—C₁₋₈ alkyl, —S(O)₂-C₁₋₆ alkyl, —C(O)NR^(d)R^(e), and        4-6-membered heteroaryl having from 1-3 heteroatom ring vertices        selected from the group consisting of O, N, and S, wherein each        of said R¹⁰ substituents is optionally substituted with 1-3 R¹²,        or two R¹⁰ on adjacent ring vertices of Ar^(e) are optionally        combined to form a 5-membered heterocyclic ring optionally        substituted with 1-2 halogens;    -   each R″ is independently selected from the group consisting of        hydroxyl, halo, cyano, —NR^(d)R^(e), —C(O)OR^(a), phenyl, C₃₋₈        cycloalkyl, and C₁₋₄ alkyl optionally substituted with        C(O)OR^(a);    -   each R¹² is independently selected from the group consisting of        halo, cyano, hydroxy, —C(O)OR^(a); and    -   each R^(a) is H or C₁₋₆ alkyl;    -   each R^(b) and Re are independently selected from the group        consisting of H, C₁₋₈ alkyl, —S(O)₂—C₁₋₆ alkyl, —C(O)OR^(a), and        —X¹—C(O)OR^(a);    -   each R^(d) and Re are independently selected from the group        consisting of H, C₁₋₈ alkyl, —S(O)₂—C₁₋₆ alkyl; and    -   provided that when G¹ and G² are each N, G³ is CH, R² is CH₃,        and R^(1a) and R^(1b) are each H, then Ar² is other than        2-thienyl, phenyl, 2-, 3- or 4-methoxyphenyl, 3- or        4-halophenyl, 2,4-dimethoxyphenyl, 2,4-dichlorophenyl or 2- or        4-methylphenyl.

In some embodiments, the adenosine A2a receptor (A2aR) or adenosine A2breceptor (A2bR) antagonist is Compound 1

or a pharmaceutically acceptable salt thereof.

In some embodiments, the adenosine A2a receptor (A2aR) or adenosine A2breceptor (A2bR) antagonist is Compound 2

or a pharmaceutically acceptable salt thereof.

In some embodiments, the adenosine A2a receptor (A2aR) or adenosine A2breceptor (A2bR) antagonist is Compound 3

or a pharmaceutically acceptable salt thereof.

In some embodiments, the adenosine A2a receptor (A2aR) and/or adenosineA2b receptor (A2bR) antagonist is a molecule described in US Pat. Pub.2018/0215730 (see also US Appl. No. 15/875,106, filed Jun. 19, 2018, thecontent of which is hereby incorporated by reference for all purposes).

In some embodiments, the A2a receptor (A2aR) and/or adenosine A2breceptor (A2bR) antagonist is AZD4635, Ciforadenant (CPI-444), NIR178,or PBF-1129.

Adenosine A3 Receptor (A3R) Antagonists. In some embodiments, the A3Rantagonist useful in the described methods is a molecule described inWO2007/063539A1 US2003/0078232, the content of each are herebyincorporated by reference for all purposes.

Types of Cancer

A person of skill in the art will recognize that oncogene driven cancerscaused by the same protein can originate in different parts of the bodyand in different cell types. In such instances, the mutation of the sameprotein in two distinct cell types or different parts of the body canresult in an oncogene driven cancer that is a different type of cancer.Using the relationship between expression levels of proteins involved inthe production of adenosine and specific mutations in particularoncogenes to guide therapy, the present disclosure provides methods thatare not limited to specific types of cancer. Thus, the presentdisclosure is useful in treating a number of different cancer typesincluding, but not limited to, cancers of the prostate, colorectum,pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary,testis, head, neck, skin (including melanoma and basal carcinoma),mesothelial lining, white blood cell (including lymphoma and leukemia)esophagus, breast (including triple negative breast cancer), muscle,connective tissue, lung (including small-cell lung carcinoma andnon-small-cell lung carcinoma), adrenal gland, thyroid, kidney, or bone;glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma,sarcoma (including Kaposi's sarcoma), choriocarcinoma, cutaneousbasocellular carcinoma, and testicular seminoma.

In some embodiments, the present disclosure provides methods fortreating a subject identified as having a specific type of oncogenedriven cancer with an agent that targets the extracellular production ofadenosine and/or an agent antagonizing the activation by adenosine ofone of its receptors and at least one additional therapeutic, examplesof which are set forth elsewhere herein.

In some embodiments of the present disclosure, the ongocene drivencancercancer is melanoma, colon cancer, pancreatic cancer, breastcancer, prostate cancer, lung cancer, leukemia, a brain tumor, lymphoma,sarcoma, ovarian cancer, head and neck cancer, cervical cancer orKaposi's sarcoma.

In some embodiments of the present disclosure, the ongocene drivencancercancer is a cancer of the thyroid, adrenal gland, mesotheliallining, bile duct, pancreas, brain, kidney, esophagus, rectum, colon,stomach, head, neck, skin, testis, ovary, lung, endometrium, eye,prostate, breast, or liver; or is glioblastoma, mesothelioma or sarcoma.

In some embodiments of the present disclosure, the ongocene drivencancercancer is a cancer of the testis, ovary, lung, endometrium oradrenal gland.

In some embodiments of the present disclosure, the ongocene drivencancercancer is a cancer of the eye, prostate, breast, kidney, liver orlung.

Combination Therapy

The present disclosure contemplates the use of the therapeutic agentsdescribed herein alone or in combination with one or more activetherapeutic agents. The additional active therapeutic agents can besmall chemical molecules; macromolecules such as proteins, antibodies,peptibodies, peptides, DNA, RNA or fragments of such macromolecules; orcellular or gene therapies. In such combination therapy, the variousactive agents frequently have different, complementary mechanisms ofaction. Such combination therapy may be especially advantageous byallowing a dose reduction of one or more of the agents, thereby reducingor eliminating the adverse effects associated with one or more of theagents. Furthermore, such combination therapy may have a synergistictherapeutic or prophylactic effect on the underlying disease, disorder,or condition.

As used herein, “combination” is meant to include therapies that can beadministered separately, for example, formulated separately for separateadministration (e.g., as may be provided in a kit), and therapies thatcan be administered together in a single formulation (i.e., a“co-formulation”).

In certain embodiments, the therapeutic agents described herein areadministered or applied sequentially, e.g., where one agent isadministered prior to one or more other agents. In other embodiments,the therapeutic agents described herein are administered simultaneously,e.g., where two or more agents are administered at or about the sametime; the two or more agents may be present in two or more separateformulations or combined into a single formulation (i.e., aco-formulation). Regardless of whether the two or more agents areadministered sequentially or simultaneously, they are considered to beadministered in combination for purposes of the present invention.

The agents that target the extracellular production of adenosine of thepresent disclosure and/or an agent antagonizing the activation byadenosine of one of its receptors may be used in combination with atleast one other (active) agent in any manner appropriate under thecircumstances. In one embodiment, treatment with the at least one activeagent and at least one an the therapeutic agents described herein ismaintained over a period of time. In another embodiment, treatment withthe at least one active agent is reduced or discontinued (e.g., when thesubject is stable), while treatment with a therapeutic agent describedherein is maintained at a constant dosing regimen. In a furtherembodiment, treatment with the at least one active agent is reduced ordiscontinued (e.g., when the subject is stable), while treatment with atherapeutic agent described herein is reduced (e.g., lower dose, lessfrequent dosing or shorter treatment regimen). In yet anotherembodiment, treatment with the at least one active agent is reduced ordiscontinued (e.g., when the subject is stable), and treatment with atherapeutic agent described herein is increased (e.g., higher dose, morefrequent dosing or longer treatment regimen). In yet another embodiment,treatment with the at least one active agent is maintained and treatmentwith the therapeutic agents described herein is reduced or discontinued(e.g., lower dose, less frequent dosing or shorter treatment regimen).In yet another embodiment, treatment with the at least one active agentand treatment with the therapeutic agents described herein are reducedor discontinued (e.g., lower dose, less frequent dosing or shortertreatment regimen).

The present disclosure provides methods for treating and/or preventingan oncogene driven cancer with an agent that targets the extracellularproduction of adenosine and/or an agent antagonizing the activation byadenosine of one of its receptors and at least one additionaltherapeutic or diagnostic agent. In some embodiments, the additionaltherapeutic or diagnostic agent is radiation, an immunomodulatory agentor chemotherapeutic agent, or diagnostic agent. Suitableimmunomodulatory agents that may be used in the present inventioninclude CD4OL, B7, and B7RP1; activating monoclonal antibodies (mAbs) tostimulatory receptors, such as, ant-CD40, anti-CD38, anti-ICOS, and4-IBB ligand; dendritic cell antigen loading (in vitro or in vivo);anti-cancer vaccines such as dendritic cell cancer vaccines;cytokines/chemokines, such as, ILL IL2, IL12, IL18, ELC/CCL19,SLC/CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFNa/b, M-CSF, IL-3,GM-CSF, IL-13, and anti-IL-10; bacterial lipopolysaccharides (LPS);indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors and immune-stimulatoryoligonucleotides.

In certain embodiments, the present disclosure includes administrationof the therapeutic agents described herein in combination with a signaltransduction inhibitor (STI). As used herein, the term “signaltransduction inhibitor” refers to an agent that selectively inhibits oneor more steps in a signaling pathway. Signal transduction inhibitors(STIs) of the present invention include: (i) bcr/abl kinase inhibitors(e.g., GLEEVEC); (ii) epidermal growth factor (EGF) receptor inhibitors,including kinase inhibitors and antibodies; (iii) her-2/neu receptorinhibitors (e.g., HERCEPTIN); (iv) inhibitors of Akt family kinases orthe Akt pathway (e.g., rapamycin); (v) cell cycle kinase inhibitors(e.g., flavopiridol); and (vi) phosphatidyl inositol kinase inhibitors.Agents involved in immunomodulation can also be used in combination withthe therapeutic agents described herein herein for the suppression oftumor growth in cancer patients.

Examples of chemotherapeutic agents include, but are not limited to,alkylating agents such as thiotepa and cyclosphosphamide; alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines suchas benzodopa, carboquone, meturedopa, and uredopa; ethylenimines andmethylamelamines including altretamine, triethylenemelamine,trietylenephosphoramide, triethylenethiophosphaoramide andtrimethylolomelamime; nitrogen mustards such as chiorambucil,chlornaphazine, cholophosphamide, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine,nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin,authramycin, azaserine, bleomycins, cactinomycin, calicheamicin,carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin,epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins,mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin,puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin,tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such asmethotrexate and 5-fluorouracil (5-FU); folic acid analogs such asdenopterin, methotrexate, pteropterin, trimetrexate; purine analogs suchas fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,5-FU; androgens such as calusterone, dromostanolone propionate,epitiostanol, mepitiostane, testolactone; anti-adrenals such asaminoglutethimide, mitotane, trilostane; folic acid replenisher such asfrolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinicacid; amsacrine;

bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol;

mitolactol; pipobroman; gacytosine; arabinoside (Ara-C);cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel and doxetaxel;chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;platinum and platinum coordination complexes such as cisplatin,carboplatin and oxaliplatin; vinblastine; etoposide (VP-16); ifosfamide;mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine;novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate;CPT11; topoisomerase inhibitors; difluoromethylornithine (DMFO);retinoic acid; esperamicins; capecitabine; anthracyclines; andpharmaceutically acceptable salts, acids or derivatives of any of theabove.

Chemotherapeutic agents also include anti-hormonal agents that act toregulate or inhibit hormonal action on tumors such as anti-estrogens,including for example tamoxifen, raloxifene, aromatase inhibiting4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone,and toremifene; and antiandrogens such as flutamide, nilutamide,bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptablesalts, acids or derivatives of any of the above. In certain embodiments,combination therapy comprises a chemotherapy regimen that includes oneor more chemotherapeutic agents. In certain embodiments, combinationtherapy comprises administration of a hormone or related hormonal agent.

Additional treatment modalities that may be used in combination with thetherapeutic agents described herein include radiotherapy, a monoclonalantibody against a tumor antigen, a complex of a monoclonal antibody andtoxin, a T-cell adjuvant, bone marrow transplant, or antigen presentingcells (e.g., dendritic cell therapy), including TLR agonists which areused to stimulate such antigen presenting cells.

In certain embodiments, the present disclosure contemplates the use ofthe therapeutic agents described herein in combination with adoptivecell therapy, a new and promising form of personalized immunotherapy inwhich immune cells with anti-tumor activity are administered to cancerpatients. Adoptive cell therapy is being explored usingtumor-infiltrating lymphocytes (TIL) and T cells engineered to express,for example, chimeric antigen receptors (CAR) or T cell receptors (TCR).Adoptive cell therapy generally involves collecting T cells from anindividual, genetically modifying them to target a specific antigen orto enhance their anti-tumor effects, amplifying them to a sufficientnumber, and infusion of the genetically modified T cells into a cancerpatient. T cells can be collected from the patient to whom the expandedcells are later reinfused (e.g., autologous) or can be collected fromdonor patients (e.g., allogeneic).

In certain embodiments, the present disclosure contemplates the use ofthe compounds described herein in combination with RNAinterference-based therapies to silence gene expression. RNAi beginswith the cleavage of longer double-stranded RNAs into small interferingRNAs (siRNAs). One strand of the siRNA is incorporated into aribonucleoprotein complex known as the RNA-induced silencing complex(RISC), which is then used to identify mRNA molecules that are at leastpartially complementary to the incorporated siRNA strand. RISC can bindto or cleave the mRNA, both of which inhibits translation.

The present disclosure contemplates the use of the inhibitors of thetherapeutic agents described herein in combination with immunecheckpoint inhibitors.

The tremendous number of genetic and epigenetic alterations that arecharacteristic of all cancers provides a diverse set of antigens thatthe immune system can use to distinguish tumor cells from their normalcounterparts. In the case of T cells, the ultimate amplitude (e.g.,levels of cytokine production or proliferation) and quality (e.g., thetype of immune response generated, such as the pattern of cytokineproduction) of the response, which is initiated through antigenrecognition by the T-cell receptor (TCR), is regulated by a balancebetween co-stimulatory and inhibitory signals (immune checkpoints).Under normal physiological conditions, immune checkpoints are crucialfor the prevention of autoimmunity (i.e., the maintenance ofself-tolerance) and also for the protection of tissues from damage whenthe immune system is responding to pathogenic infection. The expressionof immune checkpoint proteins can be dysregulated by tumors as animportant immune resistance mechanism.

T-cells have been the major focus of efforts to therapeuticallymanipulate endogenous antitumor immunity because of i) their capacityfor the selective recognition of peptides derived from proteins in allcellular compartments; ii) their capacity to directly recognize and killantigen-expressing cells (by CD8+ effector T cells; also known ascytotoxic T lymphocytes (CTLs)); and iii) their ability to orchestratediverse immune responses by CD4+ helper T cells, which integrateadaptive and innate effector mechanisms.

In the clinical setting, the blockade of immune checkpoints whichresults in the amplification of antigen-specific T cell responses hasshown to be a promising approach in human cancer therapeutics.

T cell-mediated immunity includes multiple sequential steps, each ofwhich is regulated by counterbalancing stimulatory and inhibitorysignals in order to optimize the response. While nearly all inhibitorysignals in the immune response ultimately modulate intracellularsignaling pathways, many are initiated through membrane receptors, theligands of which are either membrane-bound or soluble (cytokines). Whileco-stimulatory and inhibitory receptors and ligands that regulate T-cellactivation are frequently not over-expressed in cancers relative tonormal tissues, inhibitory ligands and receptors that regulate T celleffector functions in tissues are commonly overexpressed on tumor cellsor on non-transformed cells associated with the tumor microenvironment.The functions of the soluble and membrane-bound receptor ligand immunecheckpoints can be modulated using agonist antibodies (forco-stimulatory pathways) or antagonist antibodies (for inhibitorypathways). Thus, in contrast to most antibodies currently approved forcancer therapy, antibodies that block immune checkpoints do not targettumor cells directly, but rather target lymphocyte receptors or theirligands in order to enhance endogenous antitumor activity. [See Pardoll,(April 2012) Nature Rev. Cancer 12:252-64].

Examples of immune checkpoints (ligands and receptors), some of whichare selectively upregulated in various types of tumor cells, that arecandidates for blockade include PD1 (programmed cell death protein 1);PDL1 (PD1 ligand); BTLA (B and T lymphocyte attenuator); CTLA4(cytotoxic T-lymphocyte associated antigen 4); TIM3 (T-cell membraneprotein 3); LAG3 (lymphocyte activation gene 3); TIGIT (T cellimmunoreceptor with Ig and

ITIM domains); and Killer Inhibitory Receptors, which can be dividedinto two classes based on their structural features: i) killer cellimmunoglobulin-like receptors (KIRs), and ii) C-type lectin receptors(members of the type II transmembrane receptor family). Other lesswell-defined immune checkpoints have been described in the literature,including both receptors (e.g., the 2B4 (also known as CD244) receptor)and ligands (e.g., certain B7 family inhibitory ligands such B7-H3 (alsoknown as CD276) and B7-H4 (also known as B7—S1, B7x and VCTN1)). [SeePardoll, (April 2012) Nature Rev. Cancer 12:252-64].

The present disclosure contemplates the use of the therapeutic agentsdescribed herein in combination with inhibitors of the aforementionedimmune-checkpoint receptors and ligands, as well as yet-to-be-describedimmune-checkpoint receptors and ligands. Certain modulators of immunecheckpoints are currently available, including the PD1 and PD-L1antibodies nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck),cemiplimab (Sanofi and Regeneron), atezolizumab (Roche), durvalumab(AstraZeneca) and avelumab (Merck), whereas others are in development.

In one aspect of the present invention, the therapeutic agents describedherein are combined with an immuno-oncology agent that is (i) an agonistof a stimulatory (including a co-stimulatory) receptor or (ii) anantagonist of an inhibitory (including a co-inhibitory) signal on Tcells, both of which result in amplifying antigen-specific T cellresponses. Certain of the stimulatory and inhibitory molecules aremembers of the immunoglobulin super family (IgSF). One important familyof membrane-bound ligands that bind to co-stimulatory or co-inhibitoryreceptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1),B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.Another family of membrane bound ligands that bind to co-stimulatory orco-inhibitory receptors is the TNF family of molecules that bind tocognate TNF receptor family members, which includes CD40 and CD4OL,OX-40, OX-40L, CD70, CD27L, CD30, CD3OL, 4-1BBL, CD137 (4-1BB),TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK,RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LT13R,LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1,Lymphotoxin a/TNF13, TNFR2, TNFa, LT13R, Lymphotoxin a 1132, FAS, FASL,RELT, DR6, TROY, NGFR.

In another aspect, the immuno-oncology agent is a cytokine that inhibitsT cell activation (e.g., IL-6, IL-10, TGF-B, VEGF, and otherimmunosuppressive cytokines) or a cytokine that stimulates T cellactivation, for stimulating an immune response.

In one aspect, T cell responses can be stimulated by a combination ofthe therapeutic agents described herein and one or more of (i) anantagonist of a protein that inhibits T cell activation (e.g., immunecheckpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3,Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56,VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and/or (ii) anagonist of a protein that stimulates T cell activation such as B7-1,B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX4OL, GITR,GITRL, CD70, CD27, CD40, DR3 and CD2. Other agents that can be combinedwith the therapeutic agents described herein for the treatment of cancerinclude antagonists of inhibitory receptors on NK cells or agonists ofactivating receptors on NK cells. For example, compounds herein can becombined with antagonists of KIR, such as lirilumab.

Yet other agents for combination therapies include agents that inhibitor deplete macrophages or monocytes, including but not limited to CSF-1Rantagonists such as CSF-1R antagonist antibodies including RG7155(WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716,WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).

In another aspect, the disclosed agents that target theproteins/receptors described herein can be used with one or more ofagonistic agents that ligate positive costimulatory receptors, blockingagents that attenuate signaling through inhibitory receptors,antagonists, and one or more agents that increase systemically thefrequency of anti-tumor T cells, agents that overcome distinct immunesuppressive pathways within the tumor microenvironment (e.g., blockinhibitory receptor engagement (e.g., PD-L1/PD-1 interactions), depleteor inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g.,daclizumab) or by ex vivo anti-CD25 bead depletion), or reverse/preventT cell anergy or exhaustion) and agents that trigger innate immuneactivation and/or inflammation at tumor sites.

In one aspect, the immuno-oncology agent is a CTLA-4 antagonist, such asan antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, forexample, YERVOY (ipilimumab) or tremelimumab.

In another aspect, the immuno-oncology agent is a PD-1 antagonist, suchas an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, forexample, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), MEDI-0680(AMP-514; WO2012/145493), BGB-108, GB-226, PDR-001, mDX-400, SHR-1210,IBI-308, PF-06801591. The immuno-oncology agent may also includepidilizumab (CT-011), though its specificity for PD-1 binding has beenquestioned. Another approach to target the PD-1 receptor is therecombinant protein composed of the extracellular domain of PD-L2(B7-DC) fused to the Fc portion of IgGl, called AMP-224.

In another aspect, the immuno-oncology agent is a PD-L1 antagonist, suchas an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include,for example, MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736),atezolizumab, avelumab, BMS-936559 (WO2007/005874), MSB0010718C(WO2013/79174), KD-033, CA-327, CA-170, ALN-PDL, TSR-042, and STI-1014.

In another aspect, the immuno-oncology agent is a LAG-3 antagonist, suchas an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, forexample, BMS-986016 (WO10/19570, WO14/08218), or IMP-731 or IMP-321(WO08/132601, WO09/44273).

In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist,such as an agonistic CD137 antibody. Suitable CD137 antibodies include,for example, urelumab and PF-05082566 (WO12/32433).

In another aspect, the immuno-oncology agent is a GITR agonist, such asan agonistic GITR antibody. Suitable GITR antibodies include, forexample, BMS-986153, BMS-986156, TRX-518 (WO06/105021, WO09/009116) andMK-4166 (WO11/028683).

In another aspect, the immuno-oncology agent is an OX40 agonist, such asan agonistic OX40 antibody. Suitable OX40 antibodies include, forexample, MEDI-6383 or MEDI-6469.

In another aspect, the immuno-oncology agent is an OX4OL antagonist,such as an antagonistic OX40 antibody. Suitable OX4OL antagonistsinclude, for example, RG-7888 (WO06/029879).

In another aspect, the immuno-oncology agent is a CD40 agonist, such asan agonistic CD40 antibody. In yet another embodiment, theimmuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40antibody. Suitable CD40 antibodies include, for example, lucatumumab ordacetuzumab.

In another aspect, the immuno-oncology agent is a CD27 agonist, such asan agonistic CD27 antibody. Suitable CD27 antibodies include, forexample, varlilumab.

In another aspect, the immuno-oncology agent is MGA271 (to B7H3)(WO11/109400).

Dosing

The agents that target the extracellular production of adenosine and/oragents antagonizing the activation by adenosine of one of its receptorsof the present disclosure may be administered to a subject in an amountthat is dependent upon, for example, the goal of administration (e.g.,the degree of resolution desired); the age, weight, sex, and health andphysical condition of the subject to which the formulation is beingadministered; the route of administration; and the nature of thedisease, disorder, condition or symptom thereof The dosing regimen mayalso take into consideration the existence, nature, and extent of anyadverse effects associated with the agent(s) being administered.Effective dosage amounts and dosage regimens can readily be determinedfrom, for example, safety and dose-escalation trials, in vivo studies(e.g., animal models), and other methods known to the skilled artisan.

In general, dosing parameters dictate that the dosage amount be lessthan an amount that could be irreversibly toxic to the subject (themaximum tolerated dose (MTD)) and not less than an amount required toproduce a measurable effect on the subject. Such amounts are determinedby, for example, the pharmacokinetic and pharmacodynamic parametersassociated with ADME, taking into consideration the route ofadministration and other factors.

An effective dose (ED) is the dose or amount of an agent that produces atherapeutic response or desired effect in some fraction of the subjectstaking it. The “median effective dose” or ED50 of an agent is the doseor amount of an agent that produces a therapeutic response or desiredeffect in 50% of the population to which it is administered. Althoughthe ED50 is commonly used as a measure of reasonable expectance of anagent's effect, it is not necessarily the dose that a clinician mightdeem appropriate taking into consideration all relevant factors. Thus,in some situations the effective amount is more than the calculatedED50, in other situations the effective amount is less than thecalculated ED50, and in still other situations the effective amount isthe same as the calculated ED50.

In addition, an effective dose of agents that target the therapeuticagents described herein may be an amount that, when administered in oneor more doses to a subject, produces a desired result relative to ahealthy subject. For example, for a subject experiencing a particulardisorder, an effective dose may be one that improves a diagnosticparameter, measure, marker and the like of that disorder by at leastabout 5%, at least about 10%, at least about 20%, at least about 25%, atleast about 30%, at least about 40%, at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 90%, or morethan 90%, where 100% is defined as the diagnostic parameter, measure,marker and the like exhibited by a normal subject.

In certain embodiments, the therapeutic agents described herein may beadministered (e.g., orally) at dosage levels of about 0.01 mg/kg toabout 50 mg/kg, or about 1 mg/kg to about 25 mg/kg, of subject bodyweight per day, one or more times a day, to obtain the desiredtherapeutic effect.

For administration of an oral agent, the compositions can be provided inthe form of tablets, capsules and the like containing from 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 3.0, 5.0, 10.0,15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0,500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the activeingredient.

In additional to oral dosing, suitable routes of administration forcertain agents described herein include parenteral (e.g., intramuscular,intravenous, subcutaneous (e.g., injection or implant), intraperitoneal,intracisternal, intraarticular, intraperitoneal, intracerebral(intraparenchymal) and intracerebroventricular), and intraocular. Depotinjections, which are generally administered subcutaneously orintramuscularly, may also be utilized to release the agents describedherein over a defined period of time.

In certain embodiments, the dosage of the desired agents the therapeuticagents described herein is contained in a “unit dosage form”. The phrase“unit dosage form” refers to physically discrete units, each unitcontaining a predetermined amount of the the therapeutic agentsdescribed herein, either alone or in combination with one or moreadditional agents, sufficient to produce the desired effect. It will beappreciated that the parameters of a unit dosage form will depend on theparticular agent and the effect to be achieved.

Kits

The present disclosure also contemplates kits comprising the therapeuticagents described herein, and pharmaceutical compositions thereof Thekits are generally in the form of a physical structure housing variouscomponents, as described below, and may be utilized, for example, inpracticing the methods described above.

A kit can include one or more of the compounds disclosed herein(provided in, e.g., a sterile container), which may be in the form of apharmaceutical composition suitable for administration to a subject. Thecompounds described herein can be provided in a form that is ready foruse (e.g., a tablet or capsule) or in a form requiring, for example,reconstitution or dilution (e.g., a powder) prior to administration.When the compounds described herein are in a form that needs to bereconstituted or diluted by a user, the kit may also include diluents(e.g., sterile water), buffers, pharmaceutically acceptable excipients,and the like, packaged with or separately from the compounds describedherein. When combination therapy is contemplated, the kit may containthe several agents separately or they may already be combined in thekit. Each component of the kit may be enclosed within an individualcontainer, and all of the various containers may be within a singlepackage. A kit of the present invention may be designed for conditionsnecessary to properly maintain the components housed therein (e.g.,refrigeration or freezing).

A kit may contain a label or packaging insert including identifyinginformation for the components therein and instructions for their use(e.g., dosing parameters, clinical pharmacology of the activeingredient(s), including mechanism of action, pharmacokinetics andpharmacodynamics, adverse effects, contraindications, etc.). Labels orinserts can include manufacturer information such as lot numbers andexpiration dates. The label or packaging insert may be, e.g., integratedinto the physical structure housing the components, contained separatelywithin the physical structure, or affixed to a component of the kit(e.g., an ampule, tube or vial). In certain embodiments, the labelincludes instructions describing the products use in an oncogene drivencancer.

Labels or inserts can additionally include, or be incorporated into, acomputer readable medium, such as a disk (e.g., hard disk, card, memorydisk), optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape,or an electrical storage media such as RAM and ROM or hybrids of thesesuch as magnetic/optical storage media, FLASH media or memory-typecards. In some embodiments, the actual instructions are not present inthe kit, but means for obtaining the instructions from a remote source,e.g., via the internet, are provided.

IV. EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention, nor are theyintended to represent that the experiments below were performed or thatthey are all of the experiments that may be performed. It is to beunderstood that exemplary descriptions written in the present tense werenot necessarily performed, but rather that the descriptions can beperformed to generate data and the like of a nature described therein.Efforts have been made to ensure accuracy with respect to numbers used(e.g., amounts, temperature, etc.), but some experimental errors anddeviations should be accounted for.

Example 1 Oncogene-Driven Regulation of Adenosine Pathway Expression inMultiple Cancers

RNA and Exome sequencing data for the Pan-Cancer The Cancer Genome Atlas(TCGA) was used to analyze the association between mutations inoncogenes and the expression levels of proteins involved in theextracellular production of adenosine and/or the expression levels ofone or more adenosine receptor signaling proteins.

RNA Sequencing Data:

Raw count data for the Pan-Cancer The Cancer Genome Atlas (TCGA) weredownloaded from GDC commons (https://gdc.cancer.gov/). The raw countswere normalized using TMM (Robinson and Oshlack, 2010) in the limmapackage (Ritchie et al., 2015) to obtain log2 counts per million (CPM).Only primary tumor samples were included for downstream analyses,metastatic and normal samples were excluded. In addition, we focused onsolid tumors and excluded blood cancers like Diffuse Large B CellLymphoma (DLBCL), AML as well as Thymomas. CD73/TNAP ratio wascalculated as the ratio of log2 CPM values for CD73 and TNAP. Theresults of this analysis are displayed in FIG. 1.

Exome Sequencing Data:

299 consensus cancer drivers were identified across multiple cancertypes in TCGA (Bailey et al., 2018). The mutations (SNPs/indels) as wellas copy number alterations for the 299 genes were downloaded fromPanCancer TCGA data hosted on cBioPortal (www.cbioportal.org).

Identification of Genetic Alterations in Cancer Drivers Regulating CD73Expression:

For each cancer driver, all the alterations in a given gene werebinarized to mutant/altered or wild-type. Only those TCGA patientshaving both RNAseq and exomeSeq data were used for downstream analyses.Using linear regression analysis (Schneider et al., 2010), expressiondata of particular cancer drivers (WT or Mutant status) were used topredict the expression of CD73 or other genes in the adenosine pathwayafter adjusting the effects of individual tumor types. The estimate andp-value was computed for each gene-cancer driver pair model for everycancer driver and multiplicity correction was performed using theBenjamini-Hochberg method (Benjamin and Hochberg, 1995). The results ofthis analysis are display in FIG. 2A-E.

Survival Analysis: CD73 expression was cut at median into 2 groups—low(less than median) and high (higher than median). Cox-regression model(Mohamed Ahmed Abdelaal, 2015) was used to assess prognostic impact ofCD73 expression on the mutation status of the predicted CD73 regulatorsin overall survival (OS) and progression-free survival (PFS). Theresults of this analysis are display in FIG. 3A-D. Kaplan-Meier curvesfor EGFR WT or ALT patients with high versus low CD73 expression weregenerated using the survminer package(https://cran.r-project.org/web/packages/survminerindex.html) in R andlog-rank test was used to compute the significance between the differentgroups. The results of this analysis are displayed in FIG. 3E.

Non-Small Cell Lung Cancer (NSCLC) Pembrolizumab Cohort:

The pembrolizumab NSCLC cohort (Rizvi et al., 2018) was used forassociation of predicted cancer driver regulators of CD73 expressionwith durable clinical benefit beyond 6 months. The mutation and responsedata for these patients was downloaded from cbioportal(www.cbioportal.org). Cox regression model (Mohamed Ahmed Abdelaal,2015) was used to associate mutation status of the predicted CD73regulators with progression-free survival. The results of this analysisare display in FIG. 4.

Data Visualization and Statistics:

All plots were generated using the ggplot2 package (Wickham, 2016) in R(http://www.R-project.org). Boxplot statistics for 2-group comparisonswere computed using Wilcoxon rank sum test or t-test in the ggpubrpackage (https://www.rdocumentation.org/packages/ggpubr) in R shown inFIG. 2B-C.

REFERENCES

Bailey, M. H., Tokheim, C., Porta-Pardo, E., Sengupta, S., Bertrand, D.,Weerasinghe, A., Colaprico, A., Wendl, M. C., Kim, J., Reardon, B., etal. (2018). Comprehensive Characterization of Cancer Driver Genes andMutations. Cell 173, 371-376.e18.

Benjamini, Y., and Hochberg, Y. (1995). Controlling the False DiscoveryRate: A Practical and Powerful Approach to Multiple Testing. Journal ofthe Royal Statistical Society: Series B (Methodological) 57, 289-300.

Mohamed Ahmed Abdelaal, M. (2015). Modeling Survival Data by Using CoxRegression Model. Ajtas 4, 504-509.

Ritchie, M. E., Phipson, B., Wu, D., Hu, Y., Law, C. W., Shi, W., andSmyth, G. K. (2015). limma powers differential expression analyses forRNA-sequencing and microarray studies. Nucleic Acids Res 43, e47-e47.

Rizvi, H., Sanchez-Vega, F., La, K., Chatila, W., Jonsson, P., Halpenny,D., Plodkowski, A., Long, N., Sauter, J. L., Rekhtman, N., et al.(2018). Molecular Determinants of Response to Anti-Programmed Cell Death(PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in PatientsWith Non-Small-Cell Lung Cancer Profiled With Targeted Next-GenerationSequencing. Journal of Clinical Oncology 36, 633-641.

Robinson, M. D., and Oshlack, A. (2010). A scaling normalization methodfor differential expression analysis of RNA-seq data. Genome Biol. 11,R25.

Schneider, A., Hommel, G., and Blettner, M. (2010). Linear RegressionAnalysis. Deutsches Aerzteblatt Online 107, 776-782.

Way, G. P., Armenia, J., Luna, A., Sander, C., Mina, M., Ciriello, G.,Network, T.C.G.A.R., Caesar-Johnson, S. J., Demchok, J. A., Felau, I.,et al. (2018). Machine Learning Detects Pan-cancer Ras PathwayActivation in The Cancer Genome Atlas. CellReports 23, 172-180.e173.

Wickham, H. (2016). ggplot2 (Cham: Springer International Publishing).

Particular embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Upon reading the foregoing, description, variations of the disclosedembodiments may become apparent to individuals working in the art, andit is expected that those skilled artisans may employ such variations asappropriate. Accordingly, it is intended that the invention be practicedotherwise than as specifically described herein, and that the inventionincludes all modifications and equivalents of the subject matter recitedin the claims appended hereto as permitted by applicable law. Moreover,any combination of the above-described elements in all possiblevariations thereof is encompassed by the invention unless otherwiseindicated herein or otherwise clearly contradicted by context.

All publications, patent applications, accession numbers, and otherreferences cited in this specification are herein incorporated byreference as if each individual publication or patent application werespecifically and individually indicated to be incorporated by reference.

What is claimed is:
 1. A method of treating a subject identified ashaving an oncogene driven cancer comprising administering to saidsubject an agent targeting the extracellular production of adenosineand/or an agent antagonizing the activation by adenosine of one of itsreceptors.
 2. The method of claim 1, wherein said subject isadministered an agent targeting the extracellular production ofadenosine.
 3. The method of claim 1, wherein said subject isadministered an agent antagonizing the activation by adenosine of one ofits receptors.
 4. The method of any one of claims 1 to 3, wherein asubject identified as having an oncogene driven cancer has a mutation inat least one gene selected from the group consisting of KRAS, BRAF, MET,FUBP1, RAC1, EGFR, CDK4, CTCF, PGR, RET, RASA1, JAK1, PHF6, NF1, CIC,ARID1A, ZFHX3, ZCCHC12, GNA11, SMAD4, USP9X, CDKN2A, FAT1, PIK3R1,SCAF4, PMS2, RNF43, SMC1A, BCOR, FGFR2, COL5A1, ATM, KMT2B, CTNNB1, MYC,RAD21, PTEN, AXL, HIF1/2A, PAK4, RHOB, TBL1XR1, KEAP1, ZFP36L2, FGFR3,FOXA1, FLT3, TRAF3, RNF111, PPP2R1A, TXNIP, STAG2, RIT1, TGIF1, FOXQ1,ATR, CYSLTR2, PCBP1, PIK3R2, ASXL1, HIST1H1C, KLF5, PIK3CB, SPOP, MECOM,CACNA1A, CTNND1, DACH1, XPO1, ZNF750, FBXW7, MUC6, KDM6A, GATA3, ZBTB20,PIK3CA, RB1, SOX17, SMARCA4, KIT, CHD8, CHD4, and APOB.
 5. The method ofany one of claims 1 to 3, wherein a subject identified as having anoncogene driven cancer has a mutation in at least one gene selected fromthe group consisting of KRAS, BRAF, MET, FUBP1, RAC1, EGFR, CDK4, CTCF,PGR, RET, RASA1, JAK1, PHF6, NF1, CIC, ARID1A, ZFHX3, ZCCHC12, GNA11,SMAD4, USP9X, CDKN2A, FAT1, PIK3R1, SCAF4, PMS2, RNF43, SMC1A, BCOR,FGFR2, COL5A1, ATM, KMT2B, CTNNB1, MYC, RAD21, PTEN, AXL, HIF1/2A, andPAK4.
 6. The method of any one of claims 1 to 3, wherein a subjectidentified as having an oncogene driven cancer has a mutation in atleast one gene selected from the group consisting of EGFR, KRAS, BRAF,MET, FUBP1, CDK4, CTCF, PGR, RET, RASA1, JAK1, NF1, CIC, ARID1A, ZFHX3,SMAD4, USP9X, CDKN2A, FAT1, AXL, HIF1/2A, PAK4 and ATM.
 7. The method ofany one of claims 1 to 3, wherein a subject identified as having anoncogene driven cancer has a mutation in at least one gene selected fromthe group consisting of MYC, PMS2, CTNNB1, and SMAD4.
 8. The method ofany one of claims 1 to 3, wherein a subject identified as having anoncogene driven cancer has a mutation in at least one gene selected fromthe group consisting of KRAS, BRAF, RASA1, AXL, HIF1/2A, PAK4 and RAC1.9. The method any one of claims 1 to 3, wherein a subject identified ashaving an oncogene driven cancer has a mutation in at least one geneselected from the group consisting of EGFR, KRAS, and BRAF.
 10. Themethod of any one of claims 1, 2, or 4 to 9, wherein the agent targetingthe extracellular production of adenosine is selected from the groupconsisting of a tissue-nonspecific alkaline phosphatase (TNAP)inhibitor, a CD73 inhibitor, an ectonucleotidepyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitor, a CD38 inhibitor,and a CD39 inhibitor.
 11. The method of any one of claims 1 or 3 to 9,wherein the agent antagonizing the activation by adenosine of one of itsreceptors is an adenosine A1 receptor (AIR) antagonist, an adenosine A2areceptor (A2aR) and/or adenosine A2b receptor (A2bR) antagonist, or anadenosine A3 receptor antagonist (A3R).
 12. The method of any one ofclaims 1 or 3 to 9, wherein the agent antagonizing the activation byadenosine of one of its receptors is an adenosine A2a receptor (A2aR)and/or adenosine A2b receptor (A2bR) antagonist.
 13. The method of claim12, wherein the adenosine A2a receptor (A2aR) and/or adenosine A2breceptor (A2bR) antagonist has the Formula (I)

or a pharmaceutically acceptable salt, hydrate, or solvate thereof,wherein, G¹ is N or CR^(3a); G² is N or CR^(3b); G³ is N or CR^(3c);R^(1a), R^(ab), and R^(ac) are each independently H or C₁₋₃ alkyl;R^(1a) and R^(1b) are each independently selected from the groupconsisting of viii) H ix) C₁₋₈ alkyl optionally substituted with from1-3 R⁵ substituents, x) —X¹—O—C₁₋₈ alkyl optionally substituted withfrom 1-3 R⁵ substituents, xi) —C(O)—R⁶, xii) Y optionally substitutedwith 1-3 R⁷ substituents, and xiii) —X¹—Y optionally substituted with1-3 R⁷ substituents; or xiv) R^(1a) and R^(1b) together with thenitrogen to which they are attached form a 5-6 membered heterocycloalkylring optionally substituted with from 1-3 R⁸ substituents, wherein theheterocycloalkyl has 0-2 additional heteroatom ring vertices selectedfrom the group consisting of O, N, and S; each Y is C₃₋₈ cycloalkyl or 4to 6-membered heterocycloalkyl having 1-3 heteroatom ring verticesselected from the group consisting of O, N, and S; R² and R⁴ are eachindependently H or C₁₋₃ alkyl; Ar¹ is phenyl or a 5 to 6-memberedheteroaryl, each of which is optionally substituted with 1-3 R⁹; Ar² isphenyl or a 5 to 6-membered heteroaryl, each of which is optionallysubstituted with 1-3 R¹⁰; wherein the 5 to 6-membered heteroaryl of Ar¹and Ar² each independently have 1-3 heteroatom ring vertices selectedfrom the group consisting of O, N, and S; each X¹ is C₁₋₆ alkylene; eachR⁵ is independently selected from the group consisting of hydroxyl, C₃₋₈cycloalkyl, phenyl, —O-phenyl, —C(O)OR^(a) and oxo; each R⁶ is C₁₋₈alkyl or Y, each of which is optionally substituted with 1-3substituents selected from the group consisting of hydroxyl, —O-phenyl,phenyl, and —O—C₁₋₈ alkyl; each R⁷ is independently selected from thegroup consisting of C₁₋₈ alkyl, hydroxyl, —O—C₁₋₈ alkyl, oxo, andC(O)OR^(a); each R⁸ is independently selected from the group consistingof C₁₋₈ alkyl, hydroxyl, and oxo; each R⁹ is independently selected fromthe group consisting of C₁₋₈ alkyl, —O—C₁₋₈ alkyl, —X¹-—O—C₁₋₈ alkyl,—O—X¹—O—C₁₋₈ alkyl, —X¹—O—X¹—O—C₁₋₈ alkyl, —C(O)—OR^(a), halogen, cyano,—NR^(b)R^(c), Y, —X¹-C₃₋₈ cycloalkyl, and —X²—Z, wherein X² is selectedfrom the group consisting of C₁₋₆ alkylene, —C₁₋₆ alkylene—O—, —C(O)—,and —S(O)₂—, Z is 4 to 6-membered heterocycloalkyl having 1-3 heteroatomring vertices selected from the group consisting of O, N, and S, andwherein each of said R⁹ substituents is optionally substituted with 1-3R¹¹; each R¹⁰ is independently selected from the group consisting ofC₁₋₈ alkyl, halo, cyano, —O—C₁₋₈ alkyl, —X¹—O—C₁₋₈ alkyl, —O—X¹—O—C₁₋₈alkyl, —S(O)₂—C₁₋₆ alkyl, —C(O)NR^(d)R^(e), and 4-6-membered heteroarylhaving from 1-3 heteroatom ring vertices selected from the groupconsisting of O, N, and S, wherein each of said R¹⁰ substituents isoptionally substituted with 1-3 R¹², or two R¹⁰ on adjacent ringvertices of Ar² are optionally combined to form a 5-memberedheterocyclic ring optionally substituted with 1-2 halogens; each R¹¹ isindependently selected from the group consisting of hydroxyl, halo,cyano, —NR^(d)R^(e), —C(O)OR^(a), phenyl, C₃₋₈ cycloalkyl, and C₁₋₄alkyl optionally substituted with C(O)OR^(a); each R¹² is independentlyselected from the group consisting of halo, cyano, hydroxy, —C(O)OR^(a);and each R^(a) is H or C₁₋₆ alkyl; each R^(b) and R^(e) areindependently selected from the group consisting of H, C₁₋₈ alkyl,—S(O)₂—C₁₋₆ alkyl, —C(O)OR^(a), and —X¹—C(O)OR^(a); each R^(d) and R^(e)are independently selected from the group consisting of H, C₁₋₈ alkyl,—S(O)₂—C₁₋₆ alkyl; and provided that when G¹ and G² are each N, G³ isCH, R² is CH₃, and R^(1a) and R^(1b) are each H, then Ar² is other than2-thienyl, phenyl, 2-, 3- or 4-methoxyphenyl, 3- or 4-halophenyl,2,4-dimethoxyphenyl, 2,4-dichlorophenyl or 2- or 4-methylphenyl.
 14. Themethod of claim 12, wherein the adenosine A2a receptor (A2aR) oradenosine A2b receptor (A2bR) antagonist is Compound 1

or a pharmaceutically acceptable salt thereof.
 15. The method of claim12, wherein the adenosine A2a receptor (A2aR) or adenosine A2b receptor(A2bR) antagonist is Compound 2

or a pharmaceutically acceptable salt thereof.
 16. The method of claim12, wherein the adenosine A2a receptor (A2aR) or adenosine A2b receptor(A2bR) antagonist is Compound 3

or a pharmaceutically acceptable salt thereof.
 17. The method of claim12, wherein the adenosine A2a receptor (A2aR) and/or adenosine A2breceptor (A2bR) antagonist is selected from the group consisting ofAZD4635, Ciforadenant (CPI-444), NIR178, and PBF-1129.
 18. The method ofclaim 11, wherein the agent targeting the extracellular production ofadenosine is an A1R antagonist.
 19. The method of claim 11, wherein theagent targeting the extracellular production of adenosine is an A3Rantagonist.
 20. The method of claim 10, wherein the agent targeting theextracellular production of adenosine is a CD73 inhibitor.
 21. Themethod of claim 20, wherein the CD73 inhibitor has the Formula (i)

or a pharmaceutically acceptable salt, hydrate, or solvate thereof,wherein, each R¹ is independently selected from the group consisting ofhydrogen, optionally substituted C₁-C₆ alkyl, optionally substitutedaryl, and —C(R²R²)—O—C(O)—OR³, or two R¹ groups are optionally combinedto form a 5- to 7-membered ring; each R² is independently selected fromthe group consisting of H and optionally substituted C₁-C₆ alkyl; eachR³ is independently selected from the group consisting of H, C₁-C₆alkyl, and optionally substituted aryl; R⁵ is selected from the groupconsisting of H and optionally substituted C₁-C₆ alkyl; X is selectedfrom the group consisting of O, CH₂, and S; A is selected from the groupconsisting of:

each of which is optionally substituted with from 1 to 5 R⁶substituents, and wherein the subscript n is an integer from 0 to 3; Zis selected from the group consisting of CH₂, CHR⁶, NR⁶, and O; each R⁶is independently selected from the group consisting of H, CH₃, OH, CN,F, optionally substituted C₁-C₆ alkyl, and OC(O)—C₁-C₆ alkyl; andoptionally two R⁶ groups on adjacent ring vertices are joined togetherto form a 5- to 6-membered ring having at least one heteroatom as a ringvertex; and Het is selected from the group consisting of:

wherein the wavy line indicates the point of attachment to the remainderof the compound, and wherein: R^(a) is selected from the groupconsisting of H, NH₂, NHR⁷, NHC(O)R⁷, NR⁷R⁷, R⁷, OH, SR⁷ and OR⁷; R^(b)is selected from the group consisting of H, halogen, NH₂, NHR⁷, NR⁷R⁷,R⁷, OH, and OR⁷; R^(c) and R^(d) are independently selected from thegroup consisting of H, halogen, haloalkyl, NH₂, NHR⁷, NR⁷R⁷, R⁷, OH,OR⁷, SR⁷, SO₂R⁷, —X¹—NH₂, —X¹—NHR⁷, —X¹—NR⁷R⁷, —X¹—OH, —X¹—OR⁷, —X¹—SR⁷and —X¹—SO₂R⁷; R^(e) and R^(f) are independently selected from the groupconsisting of H, halogen, and optionally substituted C₁-C₆ alkyl; eachX¹ is C₁-C₄alkylene; and each R⁷ is independently selected from thegroup consisting of optionally substituted C₁-C₁₀ alkyl, optionallysubstituted C₂-C₁₀ alkenyl, optionally substituted C₂-C₁₀ alkynyl,optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₃-C₇cycloalkylC₁-C₄alkyl, optionally substituted 4-7 memberedcycloheteroalkyl, optionally substituted 4-7 memberedcycloheteroalkylC₁-C₄alkyl, optionally substituted aryl, optionallysubstituted arylC₁-C₄alkyl, optionally substituted arylC₂-C₄alkenyl,optionally substituted arylC₂-C₄alkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylC₁-C₄alkyl, optionallysubstituted heteroarylC₁-C₄alkenyl, optionally substitutedheteroarylC₂-C₄alkynyl, and optionally, two R⁷ groups attached to anitrogen atom are joined together to form a 4- to 7-memberedheterocyclic ring, optionally fused to an aryl ring; with the provisothat the compounds are other than those compounds wherein thecombination of X, A, and Het results in

wherein R^(g) is H or the two R^(g) groups are combined to form anacetonide; and either (1) R^(c) and R^(e) are hydrogen and R^(a) is—OEt, —OCH₂Ph, —SCH₂Ph, —NH₂, methylamino, ethylamino, dimethylamino,diethylamino, N-methyl—N-ethylamino, phenylamino, benzylamino,2-phenylethylamino, N-benzyl—N-ethylamino, dibenzylamino,4-aminobenzylamino, 4-chlorobenzylamino, 4-nitrobenzylamino, or4-sulfamoylbenzylamino; or (2) R^(e) is hydrogen, R^(a) is —NH₂, andR^(e) is bromo, chloro, aminomethyl, or thioethyl; or (3) R^(e) ishydrogen, R^(a) is benzylamino, and R^(e) is bromo.
 22. The method ofclaim 20, wherein the CD73 inhibitor is Compound A

or a pharmaceutically acceptable salt thereof.
 23. The method of claim20, wherein the CD73 inhibitor is Compound B

or a pharmaceutically acceptable salt thereof.
 24. The method of claim20, wherein the CD73 inhibitor is Compound C

or a pharmaceutically acceptable salt thereof.
 25. The method of claim20, wherein the CD73 inhibitor is selected from the group consisting ofOleclumab (MEDI-9447), CPI-006, NZV930/SRF373, BMS-986179, and TJ4309.26. The method of claim 10, wherein the agent targeting theextracellular production of adenosine is a TNAP inhibitor.
 27. Themethod of claim 10, wherein the agent targeting the extracellularproduction of adenosine is an ENPP1 inhibitor.
 28. The method of claim10, wherein the agent targeting the extracellular production ofadenosine is a CD38 inhibitor.
 29. The method of claim 10, wherein theagent targeting the extracellular production of adenosine is a CD39inhibitor.
 30. The method of any one of claims 1 to 29, furthercomprising administering one or more additional therapeutic agents. 31.The method of claim 30, wherein the additional therapeutic agent is animmune checkpoint inhibitor.
 32. The method of claim 31, wherein theimmune checkpoint inhibitor blocks the activity of at least one of PD1,PDL1, BTLA, LAG3, a B7 family member, TIM3, TIGIT or CTLA4.
 33. Themethod of claim 32, wherein the immune checkpoint is a PD1 and/or PDL1inhibitor is selected from the group consisting of pembrolizumab,nivolumab, MEDI-0680, BGB-108, GB-226, PDR-001, mDX-400, SHR-1210,IBI-308, PF-06801591, atezolizumab, durvalumab, avelumab, BMS-936559,KD-033, CA-327, CA-170, ALN-PDL, TSR-042, and STI-1014.
 34. The methodof claim 32, wherein the PD1 and/or PDL1 inhibitor is selected from thegroup consisting of pembrolizumab, nivolumab, atezolizumab, durvalumab,and avelumab.
 35. The method of claim 30, wherein the additionaltherapeutic agent is a chemotherapeutic agent.
 36. The method of claim35, wherein the chemotherapeutic agent comprises a platinum-based oranthracycline-based chemotherapeutic agent.
 37. The method of claim 36,wherein the chemotherapeutic agent is selected from the group consistingof cisplatin, carboplatin, oxaliplatin, and doxorubicin.
 38. The methodof any one of claims 1 to 37, wherein a subject identified as having anoncogene driven cancer has a mutation in at least one gene selected fromthe group consisting of EGFR, KRAS, and BRAF, and the agent targetingthe extracellular production of adenosine is a CD73 inhibitor and/or theagent antagonizing the activation by adenosine of one of its receptorsis an adenosine A2a receptor (A2aR) and/or adenosine A2b receptor (A2bR)antagonist.
 39. The method of claim 38, wherein the adenosine A2areceptor (A2aR) and/or adenosine A2b receptor (A2bR) antagonist or aCD73 inhibitor is a compound of any one of claims 13 to
 25. 40. Themethod of any one of claims 1 to 37, wherein a subject identified ashaving an oncogene driven cancer has a mutation in at least one geneselected from the group consisting of MYC, PMS2, CTNNB1, and SMAD4, andthe agent targeting the extracellular production of adenosine is a CD73inhibitor and/or the agent antagonizing the activation by adenosine ofone of its receptors is an adenosine A2a receptor (A2aR) and/oradenosine A2b receptor (A2bR) antagonist.
 41. The method of claim 40,wherein the adenosine A2a receptor (A2aR) and/or adenosine A2b receptor(A2bR) antagonist or a CD73 inhibitor is a compound of any one of claims13 to
 25. 42. The method of any one of claims 1 to 41, wherein theoncogene driven cancer is a cancer of the prostate, colon, rectum,pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary,testis, head, neck, skin (including melanoma and basal carcinoma),mesothelial lining, white blood cell (including lymphoma and leukemia),esophagus, breast (including triple negative breast cancer), muscle,connective tissue, lung (including small-cell lung carcinoma andnon-small-cell lung carcinoma), adrenal gland, thyroid, kidney, or bone;or is glioblastoma, mesothelioma, renal cell carcinoma, gastriccarcinoma, sarcoma (including Kaposi's sarcoma), choriocarcinoma,cutaneous basocellular carcinoma, or testicular seminoma.
 43. The methodof claim 42, wherein said cancer is selected from the group consistingof melanoma, colorectal cancer, pancreatic cancer, breast cancer,prostate cancer, lung cancer, leukemia, a brain tumor, lymphoma, ovariancancer, Kaposi's sarcoma, renal cell carcinoma, head and neck cancer,and esophageal cancer.
 44. The method of any one of claims 1 to 41,wherein the oncogene driven cancer is a cancer of the thyroid, adrenalgland, mesothelial lining, bile duct, pancreas, brain, kidney,esophagus, rectum, colon, stomach, head, neck, skin, testis, ovary,lung, endometrium, eye, prostate, breast, or liver; or is glioblastoma,mesothelioma or sarcoma.
 45. The method of claim 44, wherein said canceris selected from the group consisting of cancer of the thyroid, adrenalgland, mesothelial lining, bile duct, pancreas, brain, kidney,esophagus, rectum, colon, stomach, head, neck or skin; or isglioblastoma, mesothelioma or sarcoma.
 46. The method of claim 44,wherein said cancer is selected from the group consisting of cancer ofthe testis, ovary, lung, endometrium and adrenal gland.
 47. The methodof claim 44, wherein said cancer is selected from the group consistingof cancer of the eye, prostate, breast, kidney, liver and lung.
 48. Themethod of any one of claims 1 to 47, wherein the subject is a humansubject.